Synthesis, characterization, and miRNA-mediated PI3K suppressing activity of novel cisplatin-derived complexes of selenones

Abstract

New therapeutic options are crucially for most cancers, particularly those with poor clinical outcomes. Five new derivatives of cisplatin-containing selenone ligands with the general formula, cis-[Pt(NH3)2(Selenone)2](NO3)2 (1–5) were synthesized and characterized using elemental analysis, Infrared, and nuclear magnetic resonance (1H, 13C & 77Se) spectroscopy. Spectroscopic and computational data supported the coordination of selenones to platinum(II). The structures of the complexes were predicted using density functional theory calculations. Molecular docking studies were carried out using the AutoDock Tools docking program. The in vitro cytotoxicity of these complexes and cisplatin against three human cancer cell lines, HeLa, A549, and HCT116 was investigated using the MTT assay. The best candidate complex, complex 3, was subjected to mechanistic assessments, including miRNA profiling, PI3K deactivation, and induction of apoptosis. Docking studies showed that all the newly synthesized platinum(II) complexes interacted with the minor DNA groove. The synthesized complexes showed promising cytotoxic effects against the tested cell lines. Complex 3 modulated the miRNA expression signature in A549 cells. Pathway enrichment analyses of differentially expressed miRNA gene targets identified the PI3K/AKT signaling pathway as a promising target. Complex 3 inhibited PI3K activity and induced apoptosis. Collectively, our study identified promising new platinum(II) derivatives such as complex 3, paving the way for future in vitro and in vivo validations and safety studies.

Keywords

• Cisplatin
• Selenones
• Spectroscopy
• Anti-cancer agents
• Docking
• Microarray